Magnetic resonance imaging is a fairly new technique for obtaining cross-sectional pictures through the human body without exposing the patient to ionizing radiation or painful procedures, such as endoscopy. Inherent differences in observed nuclear magnetic resonance (NMR) signals from various tissues produce differences in intensity on magnetic resonance images. The clinical evaluation of MRI has been pursued by various investigators since 1980. Although clinical trials have been promising, MRI is still unable to clearly demonstrate certain pathological states. In many magnetic resonance images, considerable intensity overlap is seen among adjacent organs and between normal and pathological tissues in a single organ.
One approach to increasing image contrast is to manipulate tissue proton density (T.sub.1 and T.sub.2) properties. This can be achieved by using chemical agents that have appropriate magnetic properties and thus can enhance tissue contrast by altering the appropriate tissue magnetic (contrast) properties.
Development of effective oral contrast agents for use in MRI is needed. Presently, MRI suffers from the inability to consistently delineate intestinal structures and lesions in patients. With the exception of the rectum and esophagus, the alimentary tube and mesentery are poorly seen by MRI. Respiratory motion, air, and fluids, combined with peristalsis, significantly degrade the quality of the image. Ulcerated gastrointestinal (GI) mucosa is often indistinguishable from other pathological conditions. The same problems have mandated the use of oral contrast agents in X-ray computerized tomography. Suitable oral or rectal contrast agents (paramagnetic, ferromagnetic, and superparamagnetic) can produce a significant change in proton relaxation to permit identification of GI mucosal abnormalities, and differentiation of bowel loops from inflammatory or neoplastic intra-abdominal masses.
Preliminary research has been performed in the development of compounds for use as oral contrast agents in MRI. Mineral oil may be used to opacate bowel loops for MRI by increasing the proton density signal. However, administration of sufficient quantities of mineral oil causes significant patient morbidity. Young, et al., J. Comp. Tomogr., Vol. 5, p. 543 (1981), demonstrated the use of ferric chloride to provide opacification of the stomach after oral administration, but morbidity due to absorption of iron precludes the clinical application of this compound. Wesbey, et al., in "Dilute Oral Iron Solutions as Gastrointestinal Contrast Agents for Magnetic Resonance Imaging; Initial Clinical Experience," Magnetic Resonance Imaging. Vol. 3, pp. 57-64 (1985), and "Paramagnetic Pharmaceuticals for Magnetic Resonance Imaging." Physiolozical Chemistrv and Physics and Medical NMR Vol. 16, pp. 145-147 (1984), proposed the use of ferric ammonium citrate as a gastrointestinal contrast agent for MRI. However, absorption of iron from the ferric ammonium citrate still occurs, although at a lower rate, with systemic and gastrointestinal side effects correspondingly reduced. The latter Wesbey, et al., article also mentions the use of transition metal and rare-earth complexes of iron, manganese, gadolinium and others, as well as stable organic free radicals, in particular nitroxide free radicals, as potentially suitable diagnostic contrast agents in MRI imaging. Runge, et al., in U.S. Pat. No. 4,615,879, entitled PARTICULATE NMR CONTRAST AGENTS FOR GASTROINTESTINAL APPLICATION; "Paramagnetic Contrast Agents in Magnetic Resonance Imaging: Research at Vanderbilt University," Phvsiolozical Chemistry and Physics and Medical NMR Vol. 16, pp. 113-118 (1984); "Oral NMR Contrast Agent Development at 0.5 T.," Abstracts; Second Annual Meeting, Society for Magnetic Resonance Imaging. 2nd Annual Meeting. Orlando, Fla., Feb. 26-Mar. 2, 1984, pp. 288-289., and "Particulate Oral NMR Contrast Agents," Int. J. Nucl. Med. Biol., Vol. 12, No. 1, pp. 37-42 (1985), used insoluble gadolinium oxalate and chromium acetylacetonate in 25% Cologel.TM. (manufactured by Eli Lilly and Company, Indianapolis, Indiana), for MRI visualization of the GI tract. Runge and colleagues also suggested that the following paramagnetic insoluble compounds, used in a dispersed suspended condition, might be suitable for MRI visualization of the GI tract: iron(II) carbonate (siderite), FeCO.sub.3 ; iron silicide, FeSi; iron diphosphide Fe.sub.2 P; iron disulfide (Morcasite), FeS.sub.2 ; chromium mononitride, CrN; Gd.sub.2 (C.sub.2 O.sub.4).sub.3.10H.sub.2 O, Gd(III) oxalate; Gd(CH(COCH.sub.3).sub.2).sub.3.3H.sub.2 O, Gd(III) acetylacetonate trihydrate; copper(II) oleate, Cu(C.sub.18 H.sub.33 O.sub.2).sub.2 ; and copper xanthate, Cu(C.sub.3 H.sub.5 OS.sub.2).sub.2 ; Kornmesser, et al., "First Clinical Use of Gd-DTPA for Gastrointestinal Contrast Enhancement," Society of Magnetic Resonance in Medicine, Fifth Annual Meeting, Montreal, Quebec, Aug. 19-22, 1986, analyzed gadolinium-DTPA (Gd-DTPA) and/or ferric ammonium citrate as contrast agents. Barnhart, et al., "Orally Administered Manganese: Gastrointestinal Uptake and Potential for MRI Contrast of GI Tract," Society of Magnetic Resonance in Medicine, Fifth Annual Meeting, Montreal, Quebec, Aug. 19-22, 1986, pp. 1520-1521, investigated the toxicity of manganese, useful as a paramagnetic contrast agent, in rats. Mattrey, et al., "Perfluorohexylbromide (PFHB) as an MRI Gastrointestinal Contrast Agent for Proton Imaging," Society of Magnetic Resonance in Medicine, Fifth Annual Meeting, Montreal, Quebec, Aug. 19-22, 1986, pp. 1516-1517, investigated the use of perfluorohexylbromide (PFHB) as a paramagnetic gastrointestinal contrast agent. Magnetite particles, which are ferromagnetic compounds, have also been used in the same fashion. These particles become superparamagnetic as their sizes are reduced. These insoluble particles require very stable suspension formulations and are easily precipitated from the suspension. Zabel, et al.. "Iron Resins as Gastrointestinal Contrast Agents in MRI," Society of Magnetic Resonance in Medicine, Fifth Annual Meeting, Works in Progress, Montreal, Quebec, Aug., 1986, pp. 259-260 (1986), suggests the use of iron (Fe.sup.3+) bound to sulfonate polystyrene resin (Fe-SO.sub.3 -resin) by an ionic bond and to iminodiacetate styrene-divinylbenzene resin (Fe-IDA-resin) by a chelation bond. The major deficiency of all of these preparations is that they are not specific for any gastrointestinal disease.
Sucrose sulfate has been shown to demonstrate an antiulcer activity in experimental ulcers induced in animals (Nagashima, et al., "Selective Binding of Sucralfate to Ulcer Lesion," Arzneim-Forsch/Druz Res Vol. 30(I), No. 1, pp. 80-83 (1980)). Sucralfate, a basic aluminum sucrose sulfate, (a complex salt of polyaluminum hydroxide with a sulfated disaccharide skeleton, sold under the trademark Carafate by Marion Laboratories Inc., Kansas City, Mo.) is an effective drug for treating peptic ulcer disease and chronic gastritis. (See U.S. Pat. No. 4,668,665, entitled Formulation of Sucralfate, to Ishihara, et al; McGraw, et al., Sucralfate, Drug Intelligence and Clinical Pharmacy, Vol. 15, pp. 578-580 (July/Aug. 1981); and Nakagawa, et al., "Selective Binding of Sucralfate to Gastric Ulcer in Man," Digestive Diseases and Sciences, Vol. 26, No. 4, pp. 297-300 (Apr. 1981).) Sucralfate is believed to work primarily by forming a protective barrier preferentially over ulcerated mucosa. The sucrose sulfate molecule avidly binds to exposed protein of ulcerated tissue. Approximately six to seven times more sucralfate binds to ulcerated gastric mucosa than to unulcerated mucosa in humans. Sucralfate and potassium sucrose sulfate have been labeled with Technetium-99-m (Tc-99m) and used successfully to image GI ulcers by scintigraphy (see Vasqueg, et al., "Work in Progress. Gastro-intestinal Ulcerations: Detection Using a Technetium-99m-Labeled Ulcer-Avid Agent," Radiologv. Vol 148, pp. 227-231, (July 1983)); Vasquez, et al., "Radio-nuclide Imaging using Technetium-99m Labeled Sucralfate and Potassium Sucrose Sulfate to Detect Gastric and Duodenal Ulcers," The Journal of Nuclear Medicine and Allied Sciences. Vol. 30, No. 2.3, pp. 141-148 (1986); Garrett, et al., "Technical Considerations in Gastric Ulcer Localization Using Technetium-99m Sucralfate," Journal of Nuclear Medicine Technology. Vol. 13, No. 3, pp. 127-130 (Sept. 1985); and Goff, et al., "Detection of Esophageal Ulcerations with Technetium-99m Albumin Sucralfate," The Journal of Nuclear Medicine, Vol. 27, No. 7 (July 1986)). It is possible that this kind of preparation can also be useful for screening of early gastric carcinoma and in the evaluation of other diseases of the bowel.
The need exists in the art for contrast agents for magnetic resonance imaging of the gastrointestinal tract which are specific to gastrointestinal diseases. The instant invention provides a composition which enhances the gastrointestinal image produced by MRI by using paramagnetic, superparamagnetic and ferromagnetic substances, in combination with a sucrose sulfate preparation for imaging of specific gastrointestinal problems.